Monday, December 15, 2014

Triple-Homone Breakthrough For Obesity?

The new peptide offers a triple hormone effect in a single-cell molecule. Credit: Indiana University

The new peptide offers a triple hormone effect in a single-cell molecule.
Credit: Indiana University

This week, a group of researchers working from Munich, Germany and Indiana, USA, report, what may be a major breakthrough in the treatment of obesity and type 2 diabetes.

In their paper, published in Nature Medicine, the researchers use a range of sophisticated experiments to demonstrate that a novel peptide, which combines agonistic actions of three hormones (GLP-1, GIP and glucagon) into a single molecule, can fully reverse diabetes and reduce body weight by over 30% in mice.

Despite this just being a mouse study, the triple combination findings are no accident. Rather, these researchers have rationally designed this molecule based on the known actions of these three hormones.

As the authors describe it, their finding

predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity.”

According to their report, this “designer” peptide,

“…demonstrates supraphysiological potency and equally aligned constituent activities at each receptor, all without cross-reactivity at other related receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models.”

Similar activity in humans would indeed represent a breakthrough, potentially providing a medical treatment that may be as (if not more) potent than bariatric surgery.

While the path to human development is generally long and stony, there are at least some folks who are optimistic: the molecule has been licensed to  Marcadia Biotech Inc., now fully owned by the Swiss pharma giant Roche. 

Clearly, this will be an exciting space to watch.

@DrSharma
Edmonton, AB

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Wednesday, December 3, 2014

Does Your Liver Control Your Appetite?

Fatty Liver

Fatty Liver

The answer may well be “yes”, at least if you happen to be a mouse.

In a rather exciting study by Iliana López-Soldado and colleagues from the Institute for Research in Biomedicine, Barcelona, published in DIABETES, the researchers show that increased liver glycogen content may affect appetite (measured as food intake) and otherwise have beneficial effects on metabolism.

In their experiments, the researchers used genetically modified mice, which overexpress an enzyme (PTG) resulting in increased liver glycogen.

Not only did these animals reduce their food intake when fed a high fat diet, they also did not develop the typical glucose intolerance, elevated insulin levels and fatty liver seen in normal mice on this diet.

Apart from losing weight (associated with lower leptin levels), these animals also had lower expression of neuropeptide Y (NPY) and higher expression of propiomelanocortin (POMC) in the hypothalamus.

Thus, the authors summarize their findings as follows:

:…liver glycogen accumulation caused a reduced food intake, protected against the deleterious effects of a HFD and diminished the metabolic impact of fasting. Therefore, we propose that hepatic glycogen content be considered a potential target for the pharmacological manipulation of diabetes and obesity.”

As a number of compounds exist that may do exactly that, these studies may point to a novel pathway for the pharmacological treatment of obesity – but let’s keep in mind that the road from finding in mice to effective treatments in humans is a long and thorny road.

@DrSharma
Edmonton, AB

ResearchBlogging.orgLópez-Soldado I, Zafra D, Duran J, Adrover A, Calbó J, & Guinovart JJ (2014). Liver glycogen reduces food intake and attenuates obesity in a high-fat diet-fed mouse model. Diabetes PMID: 25277398

 

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Monday, December 1, 2014

Are Sedentary Moms Promoting Childhood Obesity?

Edward Archer, PhD, University of Alabama Birmingham

Edward Archer, PhD, University of Alabama Birmingham

Last week, Edward Archer from the University of Alabama at Birmingham (UAB), published a paper in the Mayo Clinic Proceedings (to much media fanfare), suggesting that the primary driver of childhood obesity is the shifting of nutrient energy to fetal adipose tissue as a result of increased maternal energy availability paired with decreased maternal energy expenditure, resulting in fetal pancreatic b-cell and adipocyte hyperplasia – a theory, which Edwards labels the “maternal resource hypothesis”.

The primary process for these changes, as readers of these pages will have read before, is through epigenetic modification of DNA, which, together with other non-genetic modes of transmission including learned behaviours and environmental exposures (socioenvironmental evolution), leads to “phenotypic evolution”, which Edward describes as,

“…a unidirectional, progressive alteration in ontogeny that is propagated over multiple successive generations and may be quantified as the change over time in the population mean for the trait under examination (eg, height and obesity).”

Since the beginning of the 20th century, socioevironmental factors have significantly altered the energy balance equation for humans

“Socioenvironmental evolution has altered the evolution of human energy metabolism by inducing substantial decrements in EE imposed by daily life while improving both the quality and the quantity of nutrient-energy availability.”

“For example, as thermoneutral environments became ubiquitous, the energy cost of thermoregulation declined, and improved sanitation (eg, clean water and safer food) and vaccinations decreased the energy cost of supporting parasites (eg, fleas) and resisting pathogens (eg, communicable diseases and diarrheal infections).”

Over the past century, these developments have led to profound phenotypic changes including,

“progressive and cumulative increases in height, body stature and mass, birthweight, organ mass, head circumference, fat mass/adiposity as well as decreases in the age at which adolescents attain sexual maturity…”

Archer goes on to describe some of the many factors that may have changed in the past century, whereby, he singles out sedentariness as one of the key drivers of these developments (not surprising given Archer’s background in exercise science).

Thus, although one could perhaps make very similar arguments for any number of factor that may have changed in the past century to, in turn, affect insulin resistance and ultimately energy partitioning (change in diet, sleep deprivation, increasing maternal age, endocrine disruptors, antibiotic use, gut microbiota, medication use and many other factors I ca think of), Archer chooses to elevate sedentariness to being the main culprit.

While this may or may not be the full story, it does not change the thrust of the paper, which implies that we need to look for the key drivers of childhood obesity in the changes to the maternal-fetal (and early childhood) environment that have put us on this self-perpetuating unidirectional cycle of phenotypic evolution.

Ergo, the solution lies in focussing on the health behaviours (again, Archer emphasizes the role of physical activity) of moms.

While Archer largely focusses on maternal transmission, we should perhaps not forget that there is now some also evidence implicating a role for epigenetic modification and intergenerational transmission through paternal DNA – yes, dads are getting older and more sedentary too (not to mention fatter).

I do however agree with Edward, that this line of thinking may well have important implications for how we approach this epidemic.

For one,

“…the acknowledgment that obesity is the result of non-genetic evolutionary forces and not gluttony and sloth may help to alter the moralizing and demoralizing social and scientific discourse that pervades both public and clinical settings.”

Secondly,

“Future research may be most productive if funding is directed away from naive examinations of energy balance per se and redirected to investigations of interventions that alter the competitive strategies of various tissues.”

Thirdly,

“From the standpoint of the clinician, accurate patient phenotyping (inclusive of family obstetric history and metabolic profiling) may allow the targeting of women most likely to be a part of populations that have evolved beyond the metabolic tipping point and therefore require significant preconception intervention.”

While none of this may be easier or more feasible than other current efforts, they may well point us in a different direction than conventional theories about what is driving childhood obesity.

@DrSharma
Calgary, AB

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Wednesday, November 12, 2014

5As of Obesity Management in Primary Care

sharma-obesity-5as-booklet-coverThis week I am again touring Ontario to train health professionals in the 5As of Obesity Management (Kingston, Ottawa, St. Catherines).

It is heartening to see the tremendous interest in this topic and how the message about obesity as a chronic disease resonates with health practitioners, few of who have any prior training in obesity management.

It is particularly rewarding to see how well the Canadian Obesity Network’s 5As of Obesity Management framework is received and embraced by those working in the front lines of primary care, as this is exactly the audience for which this framework is intended.

Regular readers may recall that the 5As of Obesity Management framework was developed by the Canadian Obesity Network in an elaborate undertaking involving scores of primary care providers, experts and patients from across Canada. The tools were modelled using the latest in health information design technology and extensively field tested to ensure their applicability and adaptability to primary care practice.

Rather than overloading the tools with intricate algorithms, we opted for a rather general but insightful set of principles and recommendations designed to facilitate professional interactions that seek to identify and address the key drivers and consequence of weight gain as well as help tackle the key barriers to weight management.

Indeed, the 5As of Obesity Management are steeped in a deep understanding of the complex multi-factorial nature of obesity as a chronic (often progressive) disease for which we simply have no cure.

The framework recognizes that health cannot be measured on a scale, BMI is a poor measure of health and that obesity management should be aimed at improving the overall health and well being of those living with obesity rather than simply moving numbers on the scale.

Research on the use of the 5As in primary practice has already shown significant improvements in the likelihood of obesity being addressed in primary practice.

A large prospective randomized trial on the implementation of the 5As of Obesity Management framework in primary care (the 5AsT trial) is currently underway with early results showing promising results.

I, for one, will continue promoting this framework as the basis for obesity counselling and management in primary care – at least until someone comes up with something that is distinctly better.

If you have experience with this approach or have attended one of the many education sessions on the 5As of Obesity Management offered by the Canadian Obesity Network, I’d certainly like to hear about it.

To view an introductory video on the 5As of Obesity Management click here

@DrSharma
Ottawa, ON

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Tuesday, October 28, 2014

Should A Political Prescription For Obesity Not Also Include Better Treatments?

sharma-obesity-policy1In the latest issue of the Canadian Medical Association Journal, the editors opine on the need for a political prescription for obesity – in short taxation and regulation of  high-calorie and nutrient-poor food products as the only viable approach to the obesity epidemic. As may be expected, they use the analogy of tobacco as a justification for this approach (given that actual data from government intervention on reducing the consumption of the said foods is so far lacking).

Be that as it may, what caught my attention in the article was the following passage:

“Treating obesity does not work well; preventing it would be better. The global failure to manage obesity, now considered by the American Medical Association to be a disease, may be considered a failure of the evidence-based medicine approach to treating disease….We know that most restrictive diets result in only short-term weight loss that frequently reverses and worsens in the long term, but dietary changes that are sustainable as a lifestyle choice may work. Physical activity is not enough to prevent or treat obesity and overweight, unless it is combined with some kind of dietary intervention. Family and community interventions may work somewhat better than interventions aimed at individuals, but their implementation is patchy. Bariatric surgery has good results in the treatment of morbid obesity, but its use is always going to be limited and a last resort. Pharmaceutical agents may work to some extent, but may have nasty adverse effects.”

The interesting thought here is that the authors parade the lack of effective treatment as a justification for prevention, when I would rather have used this state of affairs to call for greater investments in finding better treatments.

Not that I am not in favour of prevention – indeed, I am all for preventing heart disease, diabetes, cancer, depression, bone and joint disease and everything else.

But, at no point would I ever call for prevention as an alternative to finding better treatments for any of these conditions.

The fact that people still die of cancer should never justify us abandoning the search for better treatments – indeed, as far I can see, the whole Pink Ribbon Industry apparently focusses on “finding the cure” – not on “finding better ways to prevent breast cancer” (even if most experts believe that much of breast cancer is indeed preventable).

Just because  we still have no effective treatments for a host of other conditions, should we abandon the search for better treatments for these conditions?

In short, what irks me most about this article is not the call for prevention – indeed I am all for it!

But when the lack of effective (or safe) treatments is used to justify this call, I must disagree.

No matter how much we restrict and tax the food industry, there will always be people around, who despite their best efforts, will struggle with excess weight. Indeed, there is no reason to believe (at least not for anyone who understands the physiology of obesity) that any form of “prevention” will reverse the epidemic in those who already have the problem – i.e. in about 6 Mill Canadians. (even if we somehow miraculously reduced obesity in the population by 30% through “preventive measures” (well beyond even the most optimistic predictions) – we would still need treatments for 4 Mill Canadians – adults and kids!)

The longer we wait to find and implement effective treatments, the longer these individuals will struggle with a condition that should deserve the same efforts at treatment as we afford individuals with other “lifestyle” diseases (including heart disease, diabetes and cancer).

Let us not forget that treatments for other common conditions (e.g. hypertension, hypercholesterolemia and diabetes) were once lacking – today millions around the world benefit from these treatments – indeed, it is probably safe to say that these medications probably save more lives each year than any known efforts at regulating industry that I know of.

Indeed, if we wish to find more effective ways to manage obesity, we need to vastly increase our efforts at finding better treatments – not abandon them.

Prevention is never an alternative to also having effective treatments. The two go hand-in-hand.

@DrSharma
Edmonton, AB

 

 

 

 

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In The News

Diabetics in most need of bariatric surgery, university study finds

Oct. 18, 2013 – Ottawa Citizen: "Encouraging more men to consider bariatric surgery is also important, since it's the best treatment and can stop diabetic patients from needing insulin, said Dr. Arya Sharma, chair in obesity research and management at the University of Alberta." Read article

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